628549
research-article2016
HICXXX10.1177/2324709616628549Journal of Investigative Medicine High Impact Case ReportsChen et al
Article
Led Astray by Hemoglobin A1c: A Case of Misdiagnosis of Diabetes by Falsely Elevated Hemoglobin A1c
Journal of Investigative Medicine High Impact Case Reports January-March 2016: 1–5 © 2016 American Federation for Medical Research DOI: 10.1177/2324709616628549 hic.sagepub.com
Jean Chen, MD1,2, Amy Diesburg-Stanwood, DNP, FNP-BC2, Geza Bodor, MD2, and Neda Rasouli, MD1,2
Abstract Hemoglobin A1c (A1c) is used frequently to diagnose and treat diabetes mellitus. Therefore, it is important be aware of factors that may interfere with the accuracy of A1c measurements. This is a case of a rare hemoglobin variant that falsely elevated a nondiabetic patient’s A1c level and led to a misdiagnosis of diabetes. A 67-year-old male presented to endocrine clinic for further management after he was diagnosed with diabetes based on an elevated A1c of 10.7%, which is approximately equivalent to an average blood glucose of 260 mg/dL. Multiple repeat A1c levels remained >10%, but his home fasting and random glucose monitoring ranged from 92 to 130 mg/dL. Hemoglobin electrophoresis and subsequent genetic analysis diagnosed the patient with hemoglobin Wayne, a rare hemoglobin variant. This variant falsely elevates A1c levels when A1c is measured using cation-exchange high-performance liquid chromatography. When the boronate affinity method was applied instead, the patient’s A1c level was actually 4.7%. Though hemoglobin Wayne is clinically silent, this patient was erroneously diagnosed with diabetes and started on an antiglycemic medication. Due to this misdiagnosis, the patient was at risk of escalation in his “diabetes management” and hypoglycemia. Therefore, it is important that providers are aware of factors that may result in hemoglobin A1c inaccuracy including hemoglobin variants. Keywords diabetes mellitus, hemoglobin A1c, hemoglobin Wayne, high-performance liquid chromatography
Introduction Hemoglobin A1c (A1c) became commercially available in 1978, and the American Diabetes Association recommended its use in 1994 to assess the effectiveness of management on glycemic control by providing specific A1c goals.1 In 2010, the American Diabetes Association added A1c to clinical guidelines as a means for diagnosis of diabetes.2 Because A1c does not require fasting and can be drawn at any time of day, providers may feel that it is a more convenient tool for diagnosis of diabetes as compared to the fasting plasma glucose (FPG) test and the oral glucose tolerance test (OGTT).3,4 Currently, one could diagnose diabetes mellitus based on 2 consecutive measurements of A1c ≥6.5% with no formal recommendations to confirm the diagnosis with alternative testing, such as FPG or an OGTT.5 In this article, we present a case of falsely elevated A1c levels due to a rare hemoglobin variant, which led to the misdiagnosis of diabetes.
Case Report A 67-year-old Caucasian male with Hashimoto’s thyroiditis and spinal stenosis was referred to the endocrine clinic for
the management of uncontrolled diabetes mellitus. His primary care provider had diagnosed him with type 2 diabetes based on an elevated A1c of 10.7%, which is equivalent to an average blood glucose of 260 mg/dL. Metformin 500 mg twice daily was started and titrated to 1000 mg twice daily after one week. At the initial endocrine visit, the patient complained of fatigue, weight loss, and intermittent abdominal pain. Despite already having a low body mass index of 18, lifestyle changes were implemented, including a very low carbohydrate diet. The patient had not been monitoring his blood glucose at home. While instructing the patient on how to use a glucometer, it was noted that he had a nonfasting capillary blood glucose of 100 mg/dL. In the absence of metabolic syndrome and given his previous 1
University of Colorado School of Medicine, Aurora, CO, USA VA Eastern Colorado Health Care Systems, Denver, CO, USA
2
Corresponding Author: Neda Rasouli, MD, Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Mail Stop 8106, 12631 East 17th Avenue, Aurora, CO 80045, USA. Email: [email protected]
Creative Commons CC-BY: This article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).
2
Journal of Investigative Medicine High Impact Case Reports
Figure 1. A1c measurement by cation-exchange high-performance liquid chromatography (BioRad Variant II HPLC analysis).
high A1c with normal glucose level, decision was made to evaluate him for type 1 diabetes entering the honeymoon phase (transient β-cell remission). The patient had a C-peptide of 2.5 ng/mL with blood glucose of 102 mg/dL and negative glutamic acid decarboxylase antibodies (less than 1.0 IU/mL). These results did not support β-cell dysfunction or autoimmunity against the β-cells. Additionally, his fructosamine level was 223 µmol/L (reference range = 0-285 µmol/L), which did not reflect hyperglycemia and was consistent with his home glucose measurements of 92 to 130 mg/dL (fasting and pre/post meals). However, his A1c continued to be 10% to 11% using the BioRad Variant II high-performance liquid chromatography (HPLC) analysis (Figure 1); therefore, further investigation into the cause of this false elevation was done.
There was no history or laboratory result to support the more commonly known causes of falsely elevated A1c. These would be conditions that can decrease red blood cell (RBC) turnover, such as asplenia, B12 deficiency anemia, or folate deficiency anemia.1 He had no history to suspect the presence of a nonfunctioning spleen nor had he had a splenectomy. The patient also had normal B12 and folate levels. Though the mechanism has not been clearly identified, studies have shown an association between iron deficiency anemia and elevated A1c levels in nondiabetic patients.6-8 The patient did not suffer from anemia nor had iron studies consistent with iron deficiency. Severe hypertriglyceridemia9 and severe hyperbilirubinemia have also been previously reported to cause false elevation of A1c.1 However, this patient had a nonelevated fasting triglyceride and normal
3
Chen et al Table 1. Lab Results. HGB HCT MCV Vitamin B12 Folate Iron TIBC Ferritin Triglycerides Total bilirubin BUN Creatinine
14.6 (14.5-18.1 g/dL) 44.8 (42-54%) 89.7 (80-100 fL) 838 (220-600 pg/mL) 809 (499-1504 ng/mL) 54 (40-150 µg/dL) 322 (280-500 µg/dL) 117.9 (40-400 ng/mL) 108 (≤149 mg/dL) 0.5 (
research-article2016
HICXXX10.1177/2324709616628549Journal of Investigative Medicine High Impact Case ReportsChen et al
Article
Led Astray by Hemoglobin A1c: A Case of Misdiagnosis of Diabetes by Falsely Elevated Hemoglobin A1c
Journal of Investigative Medicine High Impact Case Reports January-March 2016: 1–5 © 2016 American Federation for Medical Research DOI: 10.1177/2324709616628549 hic.sagepub.com
Jean Chen, MD1,2, Amy Diesburg-Stanwood, DNP, FNP-BC2, Geza Bodor, MD2, and Neda Rasouli, MD1,2
Abstract Hemoglobin A1c (A1c) is used frequently to diagnose and treat diabetes mellitus. Therefore, it is important be aware of factors that may interfere with the accuracy of A1c measurements. This is a case of a rare hemoglobin variant that falsely elevated a nondiabetic patient’s A1c level and led to a misdiagnosis of diabetes. A 67-year-old male presented to endocrine clinic for further management after he was diagnosed with diabetes based on an elevated A1c of 10.7%, which is approximately equivalent to an average blood glucose of 260 mg/dL. Multiple repeat A1c levels remained >10%, but his home fasting and random glucose monitoring ranged from 92 to 130 mg/dL. Hemoglobin electrophoresis and subsequent genetic analysis diagnosed the patient with hemoglobin Wayne, a rare hemoglobin variant. This variant falsely elevates A1c levels when A1c is measured using cation-exchange high-performance liquid chromatography. When the boronate affinity method was applied instead, the patient’s A1c level was actually 4.7%. Though hemoglobin Wayne is clinically silent, this patient was erroneously diagnosed with diabetes and started on an antiglycemic medication. Due to this misdiagnosis, the patient was at risk of escalation in his “diabetes management” and hypoglycemia. Therefore, it is important that providers are aware of factors that may result in hemoglobin A1c inaccuracy including hemoglobin variants. Keywords diabetes mellitus, hemoglobin A1c, hemoglobin Wayne, high-performance liquid chromatography
Introduction Hemoglobin A1c (A1c) became commercially available in 1978, and the American Diabetes Association recommended its use in 1994 to assess the effectiveness of management on glycemic control by providing specific A1c goals.1 In 2010, the American Diabetes Association added A1c to clinical guidelines as a means for diagnosis of diabetes.2 Because A1c does not require fasting and can be drawn at any time of day, providers may feel that it is a more convenient tool for diagnosis of diabetes as compared to the fasting plasma glucose (FPG) test and the oral glucose tolerance test (OGTT).3,4 Currently, one could diagnose diabetes mellitus based on 2 consecutive measurements of A1c ≥6.5% with no formal recommendations to confirm the diagnosis with alternative testing, such as FPG or an OGTT.5 In this article, we present a case of falsely elevated A1c levels due to a rare hemoglobin variant, which led to the misdiagnosis of diabetes.
Case Report A 67-year-old Caucasian male with Hashimoto’s thyroiditis and spinal stenosis was referred to the endocrine clinic for
the management of uncontrolled diabetes mellitus. His primary care provider had diagnosed him with type 2 diabetes based on an elevated A1c of 10.7%, which is equivalent to an average blood glucose of 260 mg/dL. Metformin 500 mg twice daily was started and titrated to 1000 mg twice daily after one week. At the initial endocrine visit, the patient complained of fatigue, weight loss, and intermittent abdominal pain. Despite already having a low body mass index of 18, lifestyle changes were implemented, including a very low carbohydrate diet. The patient had not been monitoring his blood glucose at home. While instructing the patient on how to use a glucometer, it was noted that he had a nonfasting capillary blood glucose of 100 mg/dL. In the absence of metabolic syndrome and given his previous 1
University of Colorado School of Medicine, Aurora, CO, USA VA Eastern Colorado Health Care Systems, Denver, CO, USA
2
Corresponding Author: Neda Rasouli, MD, Division of Endocrinology, Metabolism and Diabetes, University of Colorado School of Medicine, Mail Stop 8106, 12631 East 17th Avenue, Aurora, CO 80045, USA. Email: [email protected]
Creative Commons CC-BY: This article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).
2
Journal of Investigative Medicine High Impact Case Reports
Figure 1. A1c measurement by cation-exchange high-performance liquid chromatography (BioRad Variant II HPLC analysis).
high A1c with normal glucose level, decision was made to evaluate him for type 1 diabetes entering the honeymoon phase (transient β-cell remission). The patient had a C-peptide of 2.5 ng/mL with blood glucose of 102 mg/dL and negative glutamic acid decarboxylase antibodies (less than 1.0 IU/mL). These results did not support β-cell dysfunction or autoimmunity against the β-cells. Additionally, his fructosamine level was 223 µmol/L (reference range = 0-285 µmol/L), which did not reflect hyperglycemia and was consistent with his home glucose measurements of 92 to 130 mg/dL (fasting and pre/post meals). However, his A1c continued to be 10% to 11% using the BioRad Variant II high-performance liquid chromatography (HPLC) analysis (Figure 1); therefore, further investigation into the cause of this false elevation was done.
There was no history or laboratory result to support the more commonly known causes of falsely elevated A1c. These would be conditions that can decrease red blood cell (RBC) turnover, such as asplenia, B12 deficiency anemia, or folate deficiency anemia.1 He had no history to suspect the presence of a nonfunctioning spleen nor had he had a splenectomy. The patient also had normal B12 and folate levels. Though the mechanism has not been clearly identified, studies have shown an association between iron deficiency anemia and elevated A1c levels in nondiabetic patients.6-8 The patient did not suffer from anemia nor had iron studies consistent with iron deficiency. Severe hypertriglyceridemia9 and severe hyperbilirubinemia have also been previously reported to cause false elevation of A1c.1 However, this patient had a nonelevated fasting triglyceride and normal
3
Chen et al Table 1. Lab Results. HGB HCT MCV Vitamin B12 Folate Iron TIBC Ferritin Triglycerides Total bilirubin BUN Creatinine
14.6 (14.5-18.1 g/dL) 44.8 (42-54%) 89.7 (80-100 fL) 838 (220-600 pg/mL) 809 (499-1504 ng/mL) 54 (40-150 µg/dL) 322 (280-500 µg/dL) 117.9 (40-400 ng/mL) 108 (≤149 mg/dL) 0.5 (
